A novel approach to combinatorial library design

We address the problem of designing a general-purpose combinatorial library to screen for pharmaceutical leads. Conventional approaches focus on diversity as the primary factor in designing such libraries. We suggest making screening libraries out of a set of pharmaceutically relevant scaffolds, with multiple analogs per scaffold. The rationale for this rests on the fact that even though the hit-rate in active series is much higher than in the database as a whole, often a large fraction of the compounds in active series are inactive. This is especially true when the series has not been optimized for the target under study. We introduce the concept of hit-rate within a series and use historic screening data to arrive at a crude estimate for it. We then use simple probability arguments to show that 50-100 compounds are required in each series in order to be nearly certain of finding at least one active compound in each true active series for any given target.     

Database diversity assessment: New ideas, concepts, and tools

We present some new ideas for characterizing and comparing largechemical databases. The comparison of the contents of large databases is nottrivial since it implies pairwise comparison of hundreds of thousands ofcompounds. We have developed methods for categorizing compounds into groupsor series based on their ring-system content, using precalculatedstructure-based hashcodes. Two large databases can then be compared bysimply comparing their hashcode tables. Furthermore, the number of distinctring-system combinations can be used as an indicator of database diversity.We also present an indepen- dent technique for diversity assessment calledthe saturation diversity approach. This method is based on picking as manymutually dissimilar compounds as possible from a database or a subsetthereof. We show that both methods yield similar results. Since the twomethods measure very different properties, this probably says more about theproperties of the databases studied than about the methods.     

Cross-Coupling of Aryllithiums with Aryl and Vinyl Halides in Flow Microreactors

The use of Pd catalysts that contained a carbene ligand, such as PEPPSI-SIPr, speeded up the Murahashi coupling of ArLi with ArBr, by enabling its integration with the Br/Li exchange of ArBr with BuLi in flow. Space integration realized the rapid cross-coupling of two different ArBr substrates. However, the cross-coupling reaction with vinyl halides could not be achieved under similar conditions. Pd(OAc)₂ was an effective catalyst, and the space integration of the Br/Li exchange of ArBr with BuLi and the Murahashi coupling with vinyl halides was successfully achieved.     

Synthesis of selenocystine derivatives from cystine by applying the transformation reaction from disulfides to diselenides

A stepwise conversion of a disulfide (SS) to a diselenide (SeSe) bond through the corresponding iodide intermediate was implemented and was applied to the synthesis of selenocystamine and l-selenocystine derivatives from cystamine and l-cystine, respectively, in moderate yields.     

Quadratisation de Certaines Structures de Poisson

On sait associer à certaines structures de Poisson surRⁿ, de 1-jet nul en 0, des actions de R² sur Rⁿ, donnéespar le ‘rotationnel’ de leur partie quadratiqueet un autre champ de vecteurs. Lorsque ces actions sont ‘nonrésonantes’ et ‘hyperboliques’, onmontre que ces structures sont ‘quadratisables’,en ce sens qu'il existe des coordonnées dans lesquelles,elles sont quadratiques. Dans le cas de la dimension 3, nosrésultats mènent à la ‘non-dégénérescence’générique des structures de Poisson quadratiquesà rotationnels inversibles. We can associate with some Poisson structures defined on Rⁿwith a zero 1-jet at zero, actions from R² on Rⁿ, given by the‘curl’ of their quadratic part and another vectorfield. Assuming that those actions are ‘hyperbolics’and without ‘resonances’, we give a normal formfor those structures. On R³, we prove that every quadratic Poissonstructure with invertible curl, is generically ‘non degenerate’.